rs61749721

chrX-154031065-G-AchrX-154031065-G-C

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_001110792.2(MECP2):c.799C>T(p.Arg267Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. R267R) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 23)
• Consequence: MECP2 NM_001110792.2 stop_gained
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:41 O:1
• Conservation: PhyloP100: 2.35

Genes affected

MECP2 (HGNC:6990): (methyl-CpG binding protein 2) DNA methylation is the major modification of eukaryotic genomes and plays an essential role in mammalian development. Human proteins MECP2, MBD1, MBD2, MBD3, and MBD4 comprise a family of nuclear proteins related by the presence in each of a methyl-CpG binding domain (MBD). Each of these proteins, with the exception of MBD3, is capable of binding specifically to methylated DNA. MECP2, MBD1 and MBD2 can also repress transcription from methylated gene promoters. In contrast to other MBD family members, MECP2 is X-linked and subject to X inactivation. MECP2 is dispensible in stem cells, but is essential for embryonic development. MECP2 gene mutations are the cause of most cases of Rett syndrome, a progressive neurologic developmental disorder and one of the most common causes of cognitive disability in females. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Oct 2015]

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 160 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-154031065-G-A is Pathogenic according to our data. Variant chrX-154031065-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 11829.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-154031065-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MECP2	NM_001110792.2	c.799C>T	p.Arg267Ter	stop_gained	3/3	ENST00000453960.7
MECP2	NM_004992.4	c.763C>T	p.Arg255Ter	stop_gained	4/4	ENST00000303391.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MECP2	ENST00000453960.7	c.799C>T	p.Arg267Ter	stop_gained	3/3	1	NM_001110792.2
MECP2	ENST00000303391.11	c.763C>T	p.Arg255Ter	stop_gained	4/4	1	NM_004992.4	P1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 23

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:41 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Rett syndrome Pathogenic:21 Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Knight Diagnostic Laboratories, Oregon Health and Sciences University	Jun 15, 2017	- -
not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, criteria provided, single submitter	curation	Centre for Population Genomics, CPG	Jan 09, 2024	This variant has been collected from RettBASE and curated to current modified ACMG/AMP criteria. Based on the classification scheme defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like Disorders Specifications to the ACMG/AMP Variant Interpretation Guidelines VCEP 3.0, this variant is classified as pathogenic. At least the following criteria are met: This variant is absent from gnomAD (PM2_Supporting). Predicted to result in loss of function, and LOF is a known mechanism of disease (PVS1). Has been observed in at least 5 individuals with phenotypes consistent with MECP2-related disease (PS4)(PP4). Is a common, recurrent pathogenic variant ,identified as a de novo occurrence in at least one individual with Rett syndrome (PM6).(PMID: 20301670 , ClinVar database Variation ID: 11829) -
Pathogenic, criteria provided, single submitter	research	Department of Medical Genetics, Sanjay Gandhi Post Graduate Institute of Medical Sciences	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	May 06, 2022	- -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital	Oct 01, 2014	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 13, 2024	- -
Pathogenic, no assertion criteria provided	clinical testing	Bioscientia Institut fuer Medizinische Diagnostik GmbH, Sonic Healthcare	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	Jun 19, 2020	This variant is also referred to in the literature as c.763C>T (p.Arg255Ter) due to use of a different reference transcript (NM_004992.3). This nonsense variant found in exon 3 of 3 is predicted to result in loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay (NMD). This variant has been previously reported as a heterozygous change in multiple unrelated individuals with classic or atypical Rett syndrome (PMID: 23270700, 28135719, 17089071, 10508514, 31535341). Functional studies have shown that this nonsense change results in a truncated protein with impaired microtubule stability and interferes with transcriptional repression (PMID: 23238081, 11058114). In addition, a mouse model containing this variant recapitulates a Rett syndrome-like phenotype (PMID: 25634563). It is absent from the gnomAD population database and thus is presumed to be rare. Based on the available evidence, the c.799C>T (p.Arg267Ter) variant is classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Seattle Children's Hospital Molecular Genetics Laboratory, Seattle Children's Hospital	Nov 18, 2019	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Neurogenetics Laboratory - MEYER, AOU Meyer	Nov 16, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Jul 28, 2017	A heterozygous nonsense variant was identified, NM_004992.3(MECP2):c.763C>T in exon 4 of the MECP2. This nonsense variant is predicted to create a change of an arginine to a stop at amino acid position 255, NM_004992.3(MECP2):p.(Arg255*). Previous studies have shown that this results in loss of function through protein truncation (Yusufzai TM. et al, 2000). This variant is not present in the gnomAD population database and it has been previously reported multiple times in patients with Rett Syndrome (ClinVar). Additionally, functional studies showed that this variant causes loss of MECP2 transcription repression and DNA binding functions (Yusufzai TM. et al, 2000) and affects microtubule dynamics in astrocytes (Delépine C. et al,2013). Additionally, other truncating variants downstream of c.763C>T in MECP2 have been reported as pathogenic in individuals with this condition (ClinVar). Based on current information, this variant has been classified as PATHOGENIC. -
Pathogenic, criteria provided, single submitter	clinical testing	3billion	Jan 03, 2022	Stop-gained (nonsense): predicted to result in a loss or disruption of normal protein function through protein truncation. Multiple pathogenic variants are reported in the predicted truncated region (PVS1_S). The variant has been reported at least twice as pathogenic/likely pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000011829, PMID:10508514). It is not observed in the gnomAD v2.1.1 dataset (PM2_M). The variant has been previously reported as de novo in a similarly affected individual (PMID: 25533962, PS2_S). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -
Pathogenic, no assertion criteria provided	curation	RettBASE	Dec 05, 2013	- -
Pathogenic, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	-	The stop gained p.R255* in MECP2 (NM_004992.4) has been reported reported in many individuals affected with Rett syndrome, including several de novo observations (Olivia Knight et al 2013). Experimental studies have shown that this nonsense change results in a truncated protein with impaired microtubule stability and transcriptional repression (Chloe Delepine et al, 2013; T M Yusufzai wt al 2020). The variant has been reported in ClinVar as Pathogenic/Likely Pathogenic. The p.R255* variant is novel (not in any individuals) in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. This variant is predicted to cause loss of normal protein function through protein truncation. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Molecular Diagnostics Lab, Nemours Children's Health, Delaware	Jul 15, 2015	Developmental arrest; Repeated hand to mouth movements; Microcephaly; Seizures; Normal development to 6 months of age -
Pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 08, 2013	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Oct 20, 2015	This nonsense variant is predicted to cause a truncated protein, which is commonly known mechanism for disease. Variant is absent from large and broad cohorts of the ExAC project while it has been reported in at least ten RTT patients. Many clinical labs and databases classify this variant as pathogenic. Functional studies showed that variant led to deficient transcriptional repression, decreased binding to methylated DNA, and impaired microtubule stability in astrocytes. Considering all, this variant has been classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Equipe Genetique des Anomalies du Developpement, Université de Bourgogne	Nov 13, 2017	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Mar 11, 2008	- -
Pathogenic, no assertion criteria provided	case-control	Medical Genetic Institute of Henan Province, Henan Provincial People’s Hospital	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Developmental and Behavioral Pediatrics, First Affiliated Hospital of Jilin University	-	- -

not provided Pathogenic:11

Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2018	- -
Pathogenic, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics and Genomics, Karolinska University Hospital	Oct 16, 2014	- -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 17, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Mar 27, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Nov 25, 2020	Published many times in association with both classic and atypical Rett syndrome (for examples, see Hoffbuhr et al., 2001; Yamada et al., 2001; Neul et al., 2008; Lima et al., 2009); Nonsense variant predicted to result in protein truncation in a gene for which loss-of-function is a known mechanism of disease; Functional studies indicate this variant affects the protein's ability to repress transcription, and it has been shown to reduce microtubule stability (Yusufzai et al., 2000; Delepine et al., 2013); Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 31512412, 31535341, 31139143, 30829465, 31134136, 30536762, 29655203, 30564305, 28135719, 28399682, 28263302, 26175308, 16077729, 27824329, 19722030, 18337588, 11524741, 11402105, 23238081, 10508514, 11058114, 25634563, 21575601, 23270700, 18174548) -
Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Mar 16, 2018	The variant creates a premature nonsense codon, and is therefore predicted to significantly disrupt the protein structure. Found in at least one patient with expected phenotype for this gene, and found in general population data at a frequency that is consistent with pathogenicity. -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Oct 23, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Mar 10, 2021	The MECP2 c.763C>T, p.Arg255Ter variant (rs61749721) induces an early termination codon and is predicted to result in a truncated protein or absent transcript. This variant is one of the most common disease causing variants of Rett syndrome (RTT) (Neul 2008), and has been associated with both classical and atypical RTT (see link to RettBASE and references therein). Functional studies showed p.Arg255Ter to be less stable in vivo and lead to deficient transcriptional repression (Yusufzai 2000). Furthermore, this variant is reported as pathogenic in ClinVar (Variation ID: 11829), and is absent from population databases (Exome Variant Server, Exome Aggregation Consortium). Therefore, this variant is considered to be pathogenic. REFERENCES Link to RettBASE: http://mecp2.chw.edu.au/cgi-bin/mecp2/views/basic.cgi?form=basic Neul JL et al. Specific mutations in methyl-CpG-binding protein 2 confer different severity in Rett syndrome. Neurology. 2008; 70(16):1313-21. Yusufzai TM et al. Functional consequences of Rett syndrome mutations on human MeCP2. Nucleic Acids Res. 2000; 28(21):4172-9. -
Pathogenic, no assertion criteria provided	clinical testing	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	Apr 03, 2015	- -
Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

Rett syndrome;C0796222:X-linked intellectual disability-psychosis-macroorchidism syndrome;C1845336:Autism, susceptibility to, X-linked 3;C1846058:Syndromic X-linked intellectual disability Lubs type;C1968556:Severe neonatal-onset encephalopathy with microcephaly Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	Jan 10, 2022	MECP2 NM_004992.3 exon 4 p.Arg255* (c.763C>T): This variant has been reported in the literature in numerous (n>100) individuals with Rett syndrome (select publications: Amir 1999 PMID:10508514, Knight 2013 PMID:23270700, McRae 2017 PMID:28135719, Hettiarachchi 2019 PMID:31535341, RettBASE). This variant is not present in large control databases but is present in ClinVar, with several labs classifying this variant as pathogenic (Variation ID:11829). Evolutionary conservation and computational predictive tools for this variant are limited or unavailable. In addition, functional studies have shown a deleterious effect of this variant (Yusufzai 2000 PMID:11058114, Delepine 2013 PMID:23238081, Pitcher 2015 PMID:25634563). However, these studies may not accurately represent in vivo biological function. The vast majority of pathogenic variants are identified in exon 4 which encodes for the methyl binding domain and transcription repression domain. This variant creates a premature stop at this codon within exon 4 which results in an absent or abnormal protein. Loss of function variants are a known mechanism of disease for this gene (Philippe 2006 16473305). In summary, this variant is classified as pathogenic based on the data above. -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	May 18, 2017	- -

Severe neonatal-onset encephalopathy with microcephaly Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Dec 25, 2023

This sequence change creates a premature translational stop signal (p.Arg255*) in the MECP2 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 232 amino acid(s) of the MECP2 protein. This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with Rett syndrome (PMID: 1241840, 10508514, 17089071, 23270700). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 11829). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this premature translational stop signal affects MECP2 function (PMID: 11058114, 23238081, 25634563). This variant disrupts a region of the MECP2 protein in which other variant(s) (p.Arg270*) have been determined to be pathogenic (PMID: 11058114, 11241840, 18174548, 23238081). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Neurodevelopmental delay Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille

-

- -

Syndromic X-linked intellectual disability Lubs type Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center

Mar 29, 2024

- -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 28, 2023

The c.763C>T (p.R255*) alteration, located in exon 4 (coding exon 3) of the MECP2 gene, results from a C to T substitution at nucleotide position 763. This changes the amino acid from an arginine (R) to a stop codon at amino acid position 255. This alteration occurs at the 3' terminus of the MECP2 gene, is not expected to trigger nonsense-mediated mRNA decay, and impacts nearly half of the protein. However, premature stop codons are typically deleterious in nature and a significant portion of the protein is affected (Ambry internal data). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This mutation has been detected in multiple individuals who meet classical clinical criteria for Rett syndrome and is a commonly reported nonsense mutation in the literature (Amir, 1999; Laccone, 2001; Li, 2007; Delépine, 2013). Based on the available evidence, this alteration is classified as pathogenic. -

Abnormality of the nervous system Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Kariminejad - Najmabadi Pathology & Genetics Center

Jul 10, 2021

- -

X-linked intellectual disability-psychosis-macroorchidism syndrome Pathogenic:1

Pathogenic, no assertion criteria provided

curation

RettBASE

Dec 05, 2013

- -

MECP2-related disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego

-

This variant is also referred to in the literature as c.763C>T (p.Arg255Ter) due to use of a different reference transcript (NM_004992.3). This nonsense variant found in exon 3 of 3 and is predicted to result in loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay (NMD). This variant has been previously reported as a heterozygous change in multiple unrelated individuals with classic or atypical Rett syndrome (PMID: 23270700, 28135719, 17089071, 10508514, 31535341). Loss-of-function variation in MECP2 is an established mechanism of disease (PMID: 22781840, 26942018, 31527487). Functional studies have shown that this nonsense change results in a truncated protein with impaired microtubule stability and interferes with transcriptional repression (PMID: 23238081, 11058114). In addition, a mouse model containing this variant recapitulates a Rett syndrome-like phenotype (PMID: 25634563). The c.799C>T (p.Arg267Ter) variant is absent from the gnomAD population database and thus is presumed to be rare. Analysis of the parental samples was negative for the variant, indicating this variant likely occurred as a de novo event. Based on the available evidence, the c.799C>T (p.Arg267Ter) variant is classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.73	D
BayesDel_noAF	Pathogenic	0.59
CADD	Pathogenic	35
DANN	Uncertain	1.0
DEOGEN2	Benign	0.36	T
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.43	T
MetaRNN	Pathogenic	0.84	D
MutationTaster	Benign	1.0	A;A;A
GERP RS		3.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs61749721; hg19: chrX-153296516; COSMIC: COSV100317851; COSMIC: COSV100317851;